Santos Daniel Ditzel, Hatjiharissi Evdoxia, Tournilhac Olivier, Chemaly Mariana Z A, Leleu Xavier, Xu Lian, Patterson Christopher, Branagan Andrew R, Manning Robert J, Ho Allen W, Hunter Zachary R, Dimmock Elizabeth A, Kutok Jeffery L, Churchill Winthrop H, Castells Mariana C, Tai Yu-Tzu, Anderson Kenneth C, Treon Steven P
Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute.
Clin Lymphoma Myeloma. 2006 May;6(6):478-83. doi: 10.3816/CLM.2006.n.029.
Alemtuzumab is a monoclonal antibody used in the treatment of CD52-expressing B-cell malignancies, including Waldenstrom's macroglobulinemia (WM). Recent studies demonstrate high levels of alemtuzumab activity in relapsed/refractory disease. One potential target of alemtuzumab is bone marrow mast cells (BMMCs), which provide growth and survival signaling for WM lymphoplasmacytic cells.
We therefore examined BMMCs (FceRI+, CD117+) from WM and other mast cell (MC) disorders for expression of CD52.
We identified cell surface antigen expression by multicolor flow cytometric analysis and found CD52 expressed on human mast-derived cell line-1 (HMC-1) and LAD2 MC lines, on BMMC from 13 of 15 patients with WM, and on BMMCs from 4 of 4 patients with systemic mastocytosis (SM). None of 4 healthy donors expressed CD52. Reverse-transcriptase polymerase chain reaction analysis confirmed CD52 expression in the HMC-1 and LAD2 MC lines, in BMMCs from 14 of 15 patients with WM, and 3 of 3 patients with SM. CD52 transcripts were also detected in BMMCs from 6 of 6 healthy donors, despite the absence of CD52 cell surface expression. Importantly, we observed high levels of alemtuzumab-mediated, antibody-dependent, cell-mediated cytotoxicity against LAD2 MCs and BMMCs from patients with WM and SM.
These studies demonstrate that CD52 is widely expressed on human MCs and WM bone marrow lymphoplasmacytic cells and provide the preclinical rationale for the use of alemtuzumab in the treatment of WM and possibly other MC-related disorders.
阿仑单抗是一种单克隆抗体，用于治疗表达CD52的B细胞恶性肿瘤，包括华氏巨球蛋白血症（WM）。最近的研究表明，阿仑单抗在复发/难治性疾病中具有较高的活性。阿仑单抗的一个潜在靶点是骨髓肥大细胞（BMMC），它为WM淋巴浆细胞提供生长和存活信号。
因此，我们检测了来自WM和其他肥大细胞（MC）疾病的BMMC（FceRI +、CD117 +）中CD52的表达。
我们通过多色流式细胞术分析确定了细胞表面抗原的表达，发现CD52在人肥大细胞系-1（HMC-1）和LAD2 MC系、15例WM患者中13例的BMMC以及4例系统性肥大细胞增多症（SM）患者中4例的BMMC上表达。4名健康供者均未表达CD52。逆转录聚合酶链反应分析证实，HMC-1和LAD2 MC系、15例WM患者中14例的BMMC以及3例SM患者中3例的BMMC中有CD52表达。尽管健康供者的BMMC没有CD52细胞表面表达，但在6名健康供者的BMMC中也检测到了CD52转录本。重要的是，我们观察到阿仑单抗介导的、抗体依赖性的、细胞介导的对WM和SM患者的LAD2 MC和BMMC的高细胞毒性。
这些研究表明，CD52在人MC和WM骨髓淋巴浆细胞上广泛表达，并为阿仑单抗用于治疗WM及可能的其他MC相关疾病提供了临床前理论依据。
